The Design and Development of an Injectable Thermoresponsive Hydrogel for Controlled Simvastatin Release in Bone...

Osteoporotic vertebrae are a uniquely challenging tissue for local delivery due to the complex geometry of cancellous bone, the proximity of the spinal cord, and the need for reliable site retention. These challenges can be met with the use of stimuli responsive, state transiting formulations by leveraging their unique capacity for minimally invasive implantation as a liquid, sol-gel transition in response to stimuli, and finally, release of a loaded therapeutic. Here, we present the formulation development of a thermosensitive methylcellulose-collagen hydrogel, functionalised with controlled release simvastatin, recently shown to enhance osteogenesis while also impeding osteoclast activity. We first optimised a formulation with collagen content of 0.4% w/v to achieve a thermosensitive system with sol-gel transition at 29 °C, shear-thinning/injectable properties, low cytotoxicity, and high biocompatibility. Incorporation of nano-hydroxyapatite for enhanced bone tissue mimicry revealed optimal performance at 100% w/collagen content, showing long-term hydrolytic stability, maintaining more than 100% of its mass after 28 days. A loading concentration of 1 mg of simvastatin to 1 g of hydrogel displayed sustained release of simvastatin over 35 days. Finally, the release of simvastatin from the hydrogel into in vitro conditions prevented the formation of osteoclasts but failed to boost osteogenesis. Together these findings reveal a series of desirable stimuli-responsive hydrogel properties, achieving minimally invasive application coupled with sustained release of a hydrophobic compound, which is potentially useful for spatially complex bone regeneration. Further this work demonstrates the challenge of dosing sustained release systems to achieve simultaneous osteogenesis and anti-osteoclastogenic effects.